(1) Field of the Invention
The present invention relates to a process for stereoselectively preparing cis-1,5-benzothiazepine derivatives, specifically a cis-form of 2-(4-methoxyphenyl)-3-acetoxy-5-(aminoalkyl)-2,3-dihydro-1,5-benzothiazepi n-4(5H)-one represented by formula (VI): ##STR2## wherein Y represents hydrogen, halogen, alkyl, alkoxy, aryl, arylalkyl, arylalkoxy or aryloxy; n is an integer of 1 to 6; and R.sup.1 represents an amino group represented by the formula: --NR.sup.1a R.sup.1b wherein R.sup.1a and R.sup.1b each independently represents hydrogen, straight or branched C.sub.1 .about.C.sub.6 alkyl or aryl which can be substituted, or R.sup.1a and R.sup.1b may form, taken together with the nitrogen to which R.sup.1a and R.sup.1b are attached, a cyclic amino group which may be substituted or an aromatic heterocyclic group which may be substituted, provided that said cyclic amino group or said aromatic heterocyclic group may further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the cyclic skeleton. The cis-1,5-benzothiazepine derivatives (VI) prepared by the process of the present invention are useful pharmaceutical compounds having a vasodilation action and a cardiac-muscle protecting action.
(2) Description of the Prior Art
As a process for preparing 1,5-benzothiazepine derivatives, an addition reaction of o-substituted thiophenol and epoxide is known (H, Kugita, H. Inoue, S. Takeo, Chem. Pharm. Bull., 18 2028 (1970); H. Inoue, S. Takeo, H. Kugita, Yakagaku Zasshi, 93 729 (1973)). As illustrated in reaction scheme 1, an o-aminothiophenol or o-nitrothiophenol derivative is reacted with an appropriately substituted glicidic ester to obtain an addition product. A ring closure of the product is then carried out through several steps to obtain compound (VII). ##STR3## In the scheme, X represents hydrogen or oxygen; R.sup.2 represents lower alkyl; and Y is as defined above.
When an o-nitrothiophenol derivative is used as a starting compound, the nitro group needs to be reduced to an amino group after the first step of the addition reaction. Compound (VII) can be converted to compound (VI) which is the objective compound of the present invention through further several steps (Reaction scheme 2) (Japanese patent application No. 302348/1991). ##STR4## In the scheme, Y, n and R.sup.1 are as defined above.
The stereochemistry (cis/trans) of compound (VI) or (VII) obtained by the process mentioned above directly reflects the stereoselectivity (threo/erythro) of the addition reaction of a substituted thiophenol and a trans-substituted glicidic ester (II). Because a cis-form of compound (VI), which is important as a medicine, is derived from a threo-form addition product, it has been desired to establish the reaction conditions and the chemical structure of starting substituted thiophenols which give stereoselectively a threo-form addition product in its reaction with compound (II).
It has been reported that o-nitrophenol derivatives stereoselectively react with compound (II) in the presence of a tin or zinc catalyst in an aprotic solvent to give a threo-form addition product (J. Med. Chem. 34, 675 (1991)). It is also known that an o-aminothiophenol derivative gives mainly a threo-form product in an aprotic solvent, while the same derivative gives as a main product an erythro-form in a polar solvent (see the above mentioned reference). However, effect of catalysts has not been investigated.